The present invention relates to novel bis(platinum) complexes and to pharmaceutical compositions containing them.
The use of platinum complexes in cancer chemotherapy is well known. A number of platinum complexes, such as Platinol, a registered trademark of cisplatin manufactured by Bristol Myers, Co., are used to treat testicular, ovarian, head and neck, and small-cell lung carcinomas. However, treatment with cisplatin may result in severe nephrotoxicity. A further clinical disadvantage is the problem of acquired drug resistance resulting in the tumor becoming refractory to treatment by the agent.
To overcome the nephrotoxic effects of cisplatin, a second-generation analog, carboplatin, was developed. Paraplatin is a registered trademark for carboplatin manufactured by Bristol-Myers, Co. Carboplatin, or [Pt(NH.sub.3).sub.2 (CBDCA)](where CBDCA is 1,1'cyclobutanedicarboxylate), is effective against the same spectrum of carcinomas as cisplatin, but exhibits a marked reduction in the nephrotoxic effects.
A number of different platinum compounds have been developed in an attempt to treat different tumors or carcinomas. For instance, U.S. Pat. No. 4,225,529 discloses the use of a cis coordination compound of platinum having four ligands which are selected from the group consisting of halides, sulphates, phosphates, nitrates, carboxylates, and same or different straight-chain amines which are coordinated to the platinum atom through their nitrogen atoms. These complexes are utilized for treating L-1210 leukemia in mice.
Also, U.S. Pat. Nos. 4,250,189, 4,553,502, and 4,565,884 relate to various Pt(II) and Pt(IV) complexes having antitumor activity. These bis(platinum) complexes are linked with a carboxylate linkage such that upon administration of these complexes to the patient, the complexes undergo rapid hydrolysis to produce two cis monoplatinum moieties which are then delivered to the active site.
However, in U.S. Pat. No. 4,797,393, a bis(platinum) complex is disclosed, which complex is delivered intact to the active site. This bis(platinum) complex has a bridging diamine or polyamine ligand and has primary or secondary amines or pyridine type nitrogens attached to the platinum complex, as well as two different or identical ligands which may be a halide, sulphate, phosphate, nitrate, carboxylate, substituted carboxylate or dicarboxylate.
Most of the synthesis of platinum analogs to date has been based on the [cis-Pt(amine).sub.2 X.sub.2 ] structure where X is a chloride or an anionic leaving group since it is believed that the cis configuration is necessary for antitumor activity in monomeric platinum complexes. A wide range of amines has been employed and a major emphasis has been on 1,2-diaminocyclohexane (which is oftentimes referred to as "dach") because laboratory studies (Burchenal et al. Biochimie, 1978, 60, 961) show that complexes derived from these amines are non-cross-resistant with cisplatin. This means that dach complexes maintain their curative activity in tumor cell lines resistant to cisplatin and the clinical advantage of such an agent should be apparent. The mechanism of action of cisplatin is generally believed to be by formation of crosslinks, especially interstrand crosslinks on DNA, producing an overall conformational change on the DNA, which eventually leads to the inhibition of replication and thus produces a cytotoxic effect as discussed in Sherman and Lippard, Chem. Review, 1987, 87, 1153 and Reedijk et al, Structure and Bonding, 1987, 67, 53.
Even though other closely related platinum complexes such as those in the trans-configuration [trans-Pt(NH.sub.3).sub.2 X.sub.2 ], trans-DDP, and monodentate complexes [(Pt(NH.sub.3).sub.3 Cl].sup.+ and [Pt(dien)Cl].sup.+, (dien=diethylenetriamine, a tridentate amine) do bind to DNA, they do not exhibit antitumor activity. This is because the trans-[Pt(NH.sub.3).sub.2 Cl.sub.2 ] and especially monodentate species such as [Pt(NH.sub.3).sub.3 Cl].sup.+ cannot form the 1,2-intrastrand crosslink.
It has been discovered that bis(platinum) complexes of U.S. Pat. No. 4,797,393 may exhibit high cytotoxic activity and are non-cross-resistant with both cisplatin and platinum-dach complexes. Their DNA binding involves interstrand crosslinks formed because of the bimetallic nature of the bis(platinum) complexes whereby each platinum atom of the bis(platinum) unit binds to opposite DNA strands. This effect has led in part to the discovery of structurally new bis(platinum) derivatives which also have activity in cisplatin-resistant lines and thus may have a broader spectrum of activity than cisplatin. Thus, there remains a need in the art to produce pharmaceutical compounds which are active in cisplatin-resistant lines.